Due to the lack of effective treatments, prostate cancer is now the second most common cause of male cancer death. However, the extremely recent elucidation of essential mechanisms governing T cell activation has revealed novel and direct methods to potential immune responses against prostate cancer. Foremost, is in vivo antibody-mediated blockade of the T cell CTLA-4 receptor (CTLA-4 blockade) which acts to facilitate T cell co-stimulatory activation, and to prolong anti-tumoral T cell responses. Hence, the experiments proposed are generally designed to test that immunotherapies based on CTLA-4 blockade can be effective for the treatment of prostate cancer. These therapies will be screened and then tested in distinct murine models that recapitulate paradigms routinely encountered in the clinical setting; such a residual prostate cancer that is recognized immediately following surgery, cancer that recurs following complete failure of hormonal treatment, and prostate cancer that is very advanced upon initial presentation. The anti-tumor effector responses raised by these therapies will be characterized. Also, novel immune manipulations such as activation of antigen present cells by CD-40 engagement, will be tested for their ability to further potentiate cancer cell death by androgen withdrawal., will be tested for its ability to convert host prostate tumors into "in situ vaccines" to further facilitate prostate cancer immunotherapy. Over the long-term, our studies should provide a solid basis for translating these therapies into the clinical setting and, moreover, help to define the most appropriate, and therefore, effective applications of these therapies for the treatment of prostate cancer.